This application claims priority of invention under 35 U.S.C. xc2xa7119 from Russian Patent Number 2129867 filed Jun. 10, 1998, and allowed May 10, 1999.
Russian patent number 2005475 (1994) discloses compositions comprising polyprenil phosphate which are reported to possess antiviral activity.
L. L. Danilov, et al., Archivum Immunologiae and Thrapiae Experimentalis, 1996, 44, 395-400 disclose a polyprenyl phosphate composition (PHOSPRENYL) that has antiviral and immunomodulatory activity. A. N. Narovlyansky, et al., Abstracts of the Second Joint Meeting of the International Cytokine Society and International Society for Interferon and Cytokine research, Jerusalem, Israel, Oct. 25-30 1998, and A. V. Sanin, et al., Abstracts of VII International Conference on AIDS, Amsterdam, the Netherlands, Jul. 19-24, 1992, also describe similar biological activity for PHOSPRENYL.
A. V. Sanin, et al. Abstracts of the meeting xe2x80x9cDolichols and Related Lipidsxe2x80x9d, Aug. 11-13, 1993, Zakopane, Poland, disclose a phosphorylated polyisoprenoid composition P16 that is reported to be a novel immunomodulatory agent and antiviral drug that might be promising in immunotherapy of infectious diseases. The composition is reported to modulate NK activity, enhance X-ray resistance, modulate GM-CSF levels, stimulate hematopoietic stem cell migration, stimulate interferon activity, and to possess mild adjuvant activity. The composition is also disclosed to possess a strong dose-dependent inhibitory activity against HIV-1 infection in MT4 cells, and to inhibit hepatitis A virus, bovine leukemia virus, adenovirus, and tick encephalitis.
Additionally, European Patent Application 0 350 801 discloses polyprenols and polyprenyl phosphates that are useful for the inhibition of tumor metastasis.
Despite the above disclosures, there is currently a need for additional therapeutic agents with antiviral and immunomodulatory activity. In particular, there is a need for agents that have improved activity or improved physical characteristics compared to known agents. For example, the PHOSPRENYL composition identified above is limited for therapeutic purposes by a low solubility in water and other polar solvents.
Applicant has discovered certain compositions that are useful for the prevention, treatment, and liquidation of consequences of diseases, including viral, chlamidial, bacterial related diseases, oncology related diseases, diseases related to the liver, gastrointestinal, urologic and reproductive systems, and diseases related to the function of the immune system. The compositions are also useful in the treatment of wounds, bums, and stresses, and are useful for medical (human) and veterinary applications. The pyrophosphate containing compositions of the invention have improved solubility compared to related known compositions, and as a result, demonstrate improved levels of activity against certain diseases.
Accordingly, the invention provides a composition comprising, 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive, or a salt thereof.
The invention also provides a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive, or a salt thereof.
The invention also provides a pharmaceutical composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof; and a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O) (OH)2 wherein m is an integer from 6-19 inclusive, or a salt thereof; and a pharmaceutically acceptable carrier.
The invention also provides a method for producing an antiviral effect in an animal comprising administering to an animal in need of such treatment, an effective antiviral amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof. As used herein xe2x80x9canimalxe2x80x9d includes for example mammals (e.g. a dog, cow, cat, or human), birds (e.g. poultry), and other animals that can effectively be treated with the compositions of the invention.
The invention also provides a method for producing an antiviral effect in an animal comprising administering to an animal in need of such treatment, an effective antiviral amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for modulating (e.g. normalizing or upregulating) the immune system of an animal comprising administering to an animal in need of such treatment, an effective immunomodulatory amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for modulating (e.g. normalizing or upregulating) the immune system of an animal comprising administering to an animal in need of such treatment, an effective immunomodulatory amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for the treatment of disease caused by distemper virus (DV), canine enteritis (parvo, rota, and corona viruses; CEV), canine infectious hepatitis (CIH), feline infectious gastroenteritis (panleukopenia, FIE), feline infectious rhinotracheitis (agentxe2x80x94herpes virus; FIR), feline infectious enteritis and peritonitis (agentxe2x80x94corona virus, FIP), swine transmissive gastroenteritis (agentxe2x80x94rotavirus; STG), murine ectromelia (ME), cattle leukemia (CL), calf mixed viral infection (agentsxe2x80x94parvo, adeno, and corona viruses; CMVI), western equestrian encephalomyelitis (WEE), or rabies (RV), comprising administering to an animal in need of such treatment, an effective therapeutic amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for the treatment of distemper virus (DV), canine enteritis (parvo, rota, and corona viruses; CEV), canine infectious hepatitis (CIH), feline infectious gastroenteritis (panleukopenia, FIE), feline infectious rhinotracheitis (agentxe2x80x94herpes virus; FIR), feline infectious enteritis and peritonitis (agentxe2x80x94corona virus, FIP), swine transmissive gastroenteritis (agentxe2x80x94rotavirus; STG), murine ectromelia (ME), cattle leukemia (CL), calf mixed viral infection (agentsxe2x80x94parvo, adeno, and corona viruses; CMVI), western equestrian encephalomyelitis (WEE), or rabies (RV), comprising administering to an animal in need of such treatment, an effective therapeutic amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for upregulating the Th1 (cell immunity) system in an animal comprising administering to an animal in need of such treatment, an effective amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for upregulating the Th1 (cell immunity) system in an animal comprising administering to an animal in need of such treatment, an effective amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method for enhancing the protective effects of a vaccine comprising administering the vaccine to an animal in need of such treatment in combination with an amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof, effective to enhance the effect of the vaccine. As used herein, xe2x80x9cenhansing the effect of a vaccinexe2x80x9d means increasing the protective effect of the vaccine by a significant and measureable amount.
The invention also provides a method for enhancing the protective effects of a vaccine comprising administering the vaccine to an animal in need of such treatment in combination with an amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof, effective to enhance the effect of the vaccine.
The invention also provides a method to correct an individual immune system comprising administering to an animal in need of such treatment, an effective amount of a composition comprising 1) polyprenol monophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]n-Oxe2x80x94P(xe2x95x90O)(OH)2 wherein n is an integer from 6-19 inclusive or a salt thereof, and 2) polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
The invention also provides a method to correct an individual immune system comprising administering to an animal in need of such treatment, an effective amount of a composition comprising polyprenol pyrophosphates of the formula Hxe2x80x94[xe2x80x94CH2-C(CH3)xe2x95x90CHxe2x80x94CH2]mxe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)xe2x80x94Oxe2x80x94P(xe2x95x90O)(OH)2 wherein m is an integer from 6-19 inclusive or a salt thereof.
It will be appreciated by those skilled in the art that polyprenes possess double bonds which may exist in cis, or trans configurations. It is to be understood that the present invention encompasses any stereoisomeric form of the polyenes as well as mixtures thereof, which possess the useful properties described herein.
Specific and preferred values listed below are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A specific composition of the invention is a composition wherein n is at least 7, wherein the polyprenol monophosphate comprises at least 90% of the weight of the composition and the and polyprenol pyrophosphate comprises less 10% of the weight.
A specific composition of the invention is a composition wherein n is 9, 10, 11, 12, 13, or 14 in greater than 50% of the polyprenol monophosphates.
A specific composition of the invention is a composition wherein m is 9, 10, 11, 12, 13, or 14 in greater than 50% of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is not more than about 2 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is not more than about 4 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is not more than about 5 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is not more than about 10 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein the weight percent of polyprenol monophosphates is not more than about 20 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein n is 11 in at least 80% of the polyprenol monophosphates present.
A specific composition of the invention is a composition wherein m is 11 in at least 80% of the polyprenol pyrophosphates present.
A specific composition of the invention is a composition wherein n is 11 in at least 80% of the polyprenol monophosphates present, and m is 11 in at least 80% of the polyprenol pyrophosphates present.
A specific composition of the invention is a composition wherein n is 11 in at least 80% of the polyprenol monophosphates present, m is 11 in at least 80% of the polyprenol pyrophosphates present, and the weight percent of polyprenol monophosphates is about 10 times greater than the weight percent of the polyprenol pyrophosphates.
A specific composition of the invention is a composition wherein n is 11 in at least 90% of the polyprenol monophosphates present.
A specific composition of the invention is a composition wherein m is 11 in at least 90% of the polyprenol pyrophosphates present.
A specific composition of the invention is a composition wherein n is 11 in at least 90% of the polyprenol monophosphates present, and m is 11 in at least 90% of the polyprenol pyrophosphates present.
A specific composition of the invention is a composition wherein n is 11 in at least 90% of the polyprenol monophosphates present, m is 11 in at least 90% of the polyprenol pyrophosphates present, and the weight percent of polyprenol monophosphates is about 10 times greater than the weight percent of the polyprenol pyrophosphates.
It is to be understood that specific compositions of the invention can also comprise up to about 10 percent by weight unphosphorylated polyprenols.
The polyprenol phosphates and pyrophosphates can be prepared from polyprenol using procedures similar to those known in the art. For example see V. N. Shibaev, and L. L. Danilov, Biochem. Cell Biol., 1992, 70, 429-437 and European Patent Application Number 0 350 801.
Polyprenols can be isolated from natural sources using procedures similar to those described by, Danilov L. L. and Shibaev V. N. (1991): Phosphopolyprenols and their glycosyl esters: chemical synthesis and biochemical application, Atta-ur-Rahman (ed): Studies in natural products chemistry, Elsevier, Amsterdamxe2x80x94Oxfordxe2x80x94New Yorkxe2x80x94Tokyo, 8, 63-114; T. Choinacki, Acta. Chem. And Biochem Polonica, 1984, 21, 3-25; and F. Takaki et al., European Patent Application 0166436A2.
Administration of the compounds as salts may be appropriate. Examples of acceptable salts include alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts, however, any salt that is non-toxic and effective when administered to the animal being treated is acceptable.
Acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently acidic compound with a suitable base affording a physiologically acceptable anion.
The compositions of the invention can be formulated as pharmaceutical compositions and administered to an animal host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient""s diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. When administered orally, the compositions of the invention can preferably be administered in a gelatin capsule.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The compositions of the invention may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active composition can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active composition in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compositions may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
Generally, the concentration of the compositions of the invention in a liquid composition, such as a lotion, will be from about 0.1-50 wt-%, preferably from about 0.5-5 wt %. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
The amount of the composition required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
The compositions are conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 xcexcM, preferably, about 1 to 50 xcexcM, most preferably, about 2 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
The compositions of the invention are poly-functional both at the cellular and at the organism levels. At the cellular level, they are incorporated in cellular membranes, enhancing their permeability. They also normalize and activate processes of cell surface glycoprotein biosynthesis, normalizing cell reproduction intracellular, and, as a result, intertussue interactions. In the organism on the whole they normalize immune system functioning, improve the function of individual organs, enhances blood generation function, and facilitate tissue regeneration.
The compositions of the invention are useful for prevention, treatment and liquidation of consequences of diseases, including viral, clamidial, bacterial, oncology, liver, gastrointestinal, urologic and reproductive system, immune system, wounds, burns, and stresses.
Following i.m. administration, the compositions of the invention enter the blood stream within about 10-15 minutes and reach a maximum concentration in the blood within one hour of administration, at which point they can be found throughout the circulatory related organs.
The antiviral activity of the compositions of the invention can be determined using assays that are known in the art, or can be determined using assays similar to those described in the following examples.
The compositions of the invention can be used for the treatment of animal diseases caused by numerous viruses including distemper virus (DV), canine enteritis (parvo, rota, and corona viruses; CEV), canine infectious hepatitis (CIH), feline infectious gastroenteritis (panleukopenia, FIE), feline infectious rhinotracheitis (agentxe2x80x94herpes virus; FIR), feline infectious enteritis and peritonitis (agentxe2x80x94corona virus, FIP), swine transmissive gastroenteritis (agentxe2x80x94rotavirus; STG), murine ectromelia (ME), cattle leukemia (CL), calf mixed viral infection (agentsxe2x80x94parvo, adeno, and corona viruses; CMVI), western equestrian encephalomyelitis (WEE), and rabies (RV).
As used in the examples hereinbelow, xe2x80x9cthe Substancexe2x80x9d is a composition of the invention wherein n is II in at least 80% of the polyprenol monophosphates present, m is 11 in at least 80% of the polyprenol pyrophosphates present, and the weight percent of polyprenol monophosphates is about 10 times greater than the weight percent of the polyprenol pyrophosphates.